Is CDON p.Pro555= (c.1665G>A) pathogenic?

CDON p.Pro555= (c.1665G>A) is classified Likely benign in CDON (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0209%, sas); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Pro555= (c.1665G>A)?

CDON p.Pro555= (c.1665G>A) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Pro555= (c.1665G>A) in the general population?

CDON p.Pro555= (c.1665G>A) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

CDON p.Pro555=

c.1665G>A · rs537471531 · VCV303514

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Conditions

holoprosencephaly 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.007	strongly benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.5	GERP -4.1
Overall
CADD	1.622	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0209% South Asian · 19/91,080 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00242% 39/1,614,082 alleles · ultra-rare exomes 32/1,461,872 · genomes 7/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,794
Remaining individualsnot grpmax-eligible	0.016%	6,251
African / African-American	0.00666%	15,004
European (non-Finnish)	0.000424%	236,000

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CDON
Protein: p.Pro555=
Coding: c.1665G>A
MANE Select: NM_001378964
dbSNP: rs537471531
Type: single nucleotide variant
Location: chr11:126005945 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB

Full CDON gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

holoprosencephaly 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDON p.Pro555Leu Uncertain significance ★ ⚠ same residue
CDON p.Pro555Ser Uncertain significance ★ ⚠ same residue
CDON c.3276+1G>T Uncertain significance ★★ same condition
CDON c.640+1G>A Uncertain significance ★★ same condition
CDON c.*1805A>G Uncertain significance ★★ same condition
CDON c.*1816C>T Uncertain significance ★★ same condition
CDON c.*2349A>C Uncertain significance ★★ same condition
CDON c.*2377T>C Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdon-p-pro555 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown